An overview of incretin clinical trials

Professor, Departments of Medicine, Biochemistry and Molecular Biology, and Molecular and Cellular Biology, Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, Texas

Chairman and Professor, Division of Family and Community Medicine, Baylor College of Medicine, Houston, Texas

Dr Garber is on the advisory board and speakers bureau for Novo Nordisk Inc.

Dr Spann has no real or apparent conflicts of interest to disclose.

This article reviews many of the key incretin clinical trials, with a focus on the efficacy and safety of glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors compared with placebo and other glucose-lowering agents used as comparators. These agents have been tested either as monotherapy or in combination with one or more oral antidiabetic drugs (OADs). The article also discusses some of the important clinical differences between GLP-1 receptor agonists and DPP-4 inhibitors.

  Introduction

Exenatide (Byetta), a twice-daily injectable GLP-1 receptor agonist, was approved in 2005 by the FDA for the treatment of type 2 diabetes mellitus (T2DM). Exenatide is derived from exendin-4, which is found in saliva of the Gila monster and is 53% homologous to human GLP-1. Consequently, exenatide is less susceptible to DPP-4 degradation than is native GLP-1, and it has a mean half-life of 2.4 hours, compared with about 2 minutes for native GLP-1.^1-2 Exenatide is indicated for patients with T2DM in combination with either metformin, a sulfonylurea, a thiazolidinedione (TZD), a combination of metformin and a TZD, or a combination of metformin and a sulfonylurea (TABLE 1). Exenatide is not recommended for patients with end-stage renal disease or severe renal impairment.

Sitagliptin (Januvia), the only oral DPP-4 inhibitor commercially available, was approved in 2006. Sitagliptin is indicated as an adjunct to diet and exercise and in combination with one or more OADs to improve glycemic control in adults with T2DM. A reduction in the dose of sitagliptin is recommended in patients with moderate to severe renal insufficiency or end-stage renal disease.³ Severe allergic and hypersensitivity reactions to sitagliptin have been documented in postmarketing reports.³

Other agents under review by the FDA or in phase 3 clinical trials include exenatide long-acting release (LAR) and the human GLP-1 analog liraglutide, which is 97% homologous to human GLP-1, as well as the DPP-4 inhibitors vildagliptin, alogliptin, and saxagliptin. Phase 2 trials have also been completed with the GLP-1 receptor agonists taspoglutide and albiglutide and various other DPP-4 inhibitors.

The GLP-1 receptor agonists and the DPP-4 inhibitors have been studied extensively in clinical trials, both in treatment-naïve patients and as second-line therapy for patients who have been unsuccessful in achieving glycemic control with one or more glucose-lowering agents. Because of differences in trial design and the current lack of head-to-head trial data, direct comparison between and among the GLP-1 receptor agonists and DPP-4 inhibitors is not possible at present. Advancing experience suggests that incretins need not be used solely as second-line therapy and can be used earlier in treatment when some β-cell function is still intact.

Overview of selected GLP-1 receptor agonists and DPP-4 inhibitors

  The GLP-1 receptor agonists

Exenatide

Exenatide, a twice-daily injectable, has been studied as monotherapy and in combination with most of the oral glucose-lowering drugs. As monotherapy in drug-naïve patients with T2DM, exenatide 5 mcg twice daily for 4 weeks followed by 10 mcg twice daily for 20 weeks resulted in reductions in the mean levels of A1C of 0.9% and fasting plasma glucose (FPG) of 18 mg/dL compared with reductions of 0.2% (P=.0004) and 5 mg/dL (P=.016) for placebo, respectively.⁴ (See TABLE, “Clinical trials of the glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes,” posted with this supplement at www.jfponline.com.) Body weight decreased by 3.1 kg with exenatide and by 1.4 kg with placebo (P=.0003). Most treatment-emergent adverse events were mild or moderate. A hypoglycemic episode was reported in 3.8% and 1.3% of patients, respectively, with no occurrence of severe hypoglycemia.

When added to other glucose-lowering agents, exenatide is effective in further lowering glucose. Three 30-week randomized, blinded, placebo-controlled phase 3 trials investigated the addition of exenatide 5 or 10 mcg twice daily to either a sulfonylurea, metformin, or both. Exenatide was administered within 15 minutes of the morning and evening meals.^5-7 The 10 mcg dose was titrated from an initial 5-mcg dose. In the exenatide 5 mcg groups, A1C levels were reduced by 0.4% to 0.6% (P<.001 to P<.0001 vs placebo) and 0.8% to 0.9% in the 10 mcg groups (P<.001 to P<.0001 vs placebo). A1C levels increased 0.1% to 0.2% in the placebo groups. FPG levels were reduced by 5 to 9 mg/dL (P=NS to P<.0001 vs placebo) and by 10 to 11 mg/dL (P<.05 to P<.0001 vs placebo) in the exenatide 5 and 10 mcg groups, respectively, compared with an increase of 7 to 14 mg/dL in the placebo groups. The only combination that did not significantly lower FPG compared with placebo was exenatide 5 mcg twice daily plus a sulfonylurea.⁵ Body weight decreased by 0.9 to 1.2 kg and 1.6 to 2.6 kg over the 30-week period in the exenatide 5 mcg and 10 mcg groups, respectively, compared with a decrease in body weight of 0.3 kg to 0.9 kg (P≤.01 to P≤.001 vs placebo for both doses of exenatide). Postprandial plasma glucose (PPG) levels also were 34% lower from baseline in each exenatide group compared to 9% lower in the placebo group (P≤.03 and P≤.004 vs placebo, respectively).⁶

When combined with metformin, the low incidence of minor hypoglycemia (5%) was comparable for both exenatide and placebo.⁶ However, when combined with a sulfonylurea, the incidence of mild to moderate hypoglycemia increased in 14% and 36% of patients receiving exenatide 5 and 10 mcg, respectively, vs 3% with placebo.⁵ A similar increase in the incidence of mild to moderate hypoglycemia was observed when exenatide was combined with metformin and a sulfonylurea.⁷ The study was completed by 69% to 81% of patients.^5-7 Nausea was observed in 36% to 39% of patients in the exenatide 5-mcg group, 45% to 51% in the exenatide 10 mcg group, and 7% to 23% in the placebo groups. Among patients who received exenatide, 41% to 49% developed anti-exenatide antibodies with high titres reported in 6-9% of patients.^5-7

An open-label, 52-week extension of these trials in overweight patients established the durability of exenatide in maintaining glycemic control (FIGURE 1).⁸ Of the 1446 patients randomized to treatment in the placebo-controlled trials, 314 (22%) elected to enter the open-label extension; of these, 57% completed the 82 weeks of treatment. At 82 weeks, 48% of participants remaining in the trial achieved an A1C ≤7%, compared with 39% of participants at 30 weeks. Similarly, weight loss continued over the 82 weeks; mean weight loss at 30 and 82 weeks was 2.1 and 4.4 kg, respectively. Nausea occurred in 15% of patients by the end of the 82 weeks.

Although a recent study confirmed the durability of exenatide for improving glycemic control (0.8% decrease in A1C), weight loss (3.67 kg), and improvements in β-cell function over 52 weeks, these variables returned to pretreatment values following a 12-week washout period.⁹ This suggests that ongoing treatment with exenatide is required to sustain these benefits.

Exenatide has also been investigated in patients with T2DM suboptimally controlled with a TZD with or without metformin. In a double-blind study by Zinman et al, patients were randomized to placebo (n=112) or exenatide 5 mcg (n=121) twice daily for 4 weeks, after which the exenatide group received 10 mcg twice daily for 12 weeks; previous therapies were continued.¹⁰ At 16 weeks, A1C decreased by a mean of 0.9% in the exenatide group and increased by 0.1% in the placebo group (P<.001). Similarly, FPG was reduced in the exenatide group by 29 mg/dL and increased in the placebo group by 2 mg/dL (P<.001). Pancreatic β-cell function as assessed by the homeostasis model of assessment (HOMA) increased by 19% in the exenatide group, but decreased by 6% in the placebo group (P=.005). Body weight was reduced by approximately 2 kg in the exenatide group, but was unchanged in the placebo group (P<.001). Twenty-nine percent of the exenatide and 14% of the placebo patients withdrew from the trial. A treatment-emergent adverse event (AE) led to withdrawal in 16% and 2% of the exenatide and placebo patients, with nausea the main cause for withdrawal in 9% and 1%, respectively. Nausea (40% exenatide vs 15% placebo) was generally mild or moderate and intermittent, occurring most often after a dose increase but declining over time. Forty percent of the exenatide patients tested positive for anti-exenatide antibodies.

The LAR formulation of exenatide has been studied in 45 adult patients with T2DM suboptimally controlled with metformin 500 to 2250 mg per day or diet and exercise alone.¹¹ Patients were randomized to exenatide LAR 0.8 or 2 mg or placebo administered subcutaneously once weekly by study site personnel for 15 weeks; all but 2 patients continued their prior treatment. At the end of 15 weeks, FPG levels were reduced by 43 and 40 mg/dL in the exenatide 0.8 and 2 mg groups, respectively, but increased by 18 mg/dL in the placebo group (both P<.05 vs placebo). A1C levels decreased from 8.6% to 7.2% and from 8.3% to 6.6% in the exenatide LAR 0.8- and 2-mg groups, respectively, but increased from 8.6% to 9.0% in the placebo group (both P<.05 vs placebo). Body weight was reduced by 3.8 kg from baseline to week 15 in the exenatide LAR 2 mg group (P<.05 vs placebo) but did not change in the exenatide 0.8 mg or placebo groups. None of the exenatide patients withdrew, whereas 2 placebo patients withdrew, 1 due to an AE. Nausea occurred in 19% to 27% of the exenatide patients and 15% of the placebo patients. Furthermore, with exenatide LAR, gastroenteritis was reported in 13% to 19%, and injection site bruising occurred in 7% to 13%, compared with no reports in those treated with placebo. Sixty-seven percent of the exenatide patients exhibited anti-exenatide antibodies.

Exenatide LAR has been compared with exenatide twice daily in patients who did not achieve acceptable glycemic control with diet and exercise or one or more oral glucose-lowering agents.¹² After 30 weeks, a mean reduction in A1C of 1.9% was observed in the exenatide LAR group compared with 1.5% in the exenatide twice-daily group (P=.002). Similarly, the reduction in FPG was greater in the exenatide LAR group compared with the exenatide twice-daily group (-42 mg/dL vs -25 mg/dL, respectively; P<.0001). Body weight decreased by about 4 kg in both groups. Nausea was observed in 26% and 35% of participants, respectively. No episodes of major hypoglycemia were reported.

Liraglutide

A single amino acid substitution and the addition of an acyl side chain make liraglutide 97% homologous to native human GLP-1. These alterations extend the elimination half-life to 13 hours following subcutaneous administration, thereby providing 24-hour glycemic control with once-daily administration.¹³

As with exenatide and the DPP-4 inhibitors, once-daily liraglutide has been studied as either monotherapy or in combination with either metformin, a sulfonylurea (glimepiride), metformin plus a TZD, or metformin plus a sulfonylurea in various randomized trials.

One 14-week, phase 2, randomized, double-blind monotherapy trial with liraglutide recruited subjects who had not achieved glycemic control with diet or one OAD.^14-17 Following discontinuation of previous OADs, subjects received liraglutide 0.65, 1.25, or 1.9 mg or placebo, once daily for 14 weeks.¹⁴ The A1C levels decreased by 1.0%, 1.4%, and 1.5% in the liraglutide groups, respectively, and increased by 0.3% in the placebo group (all P<.0001 vs placebo). Compared with baseline, the placebo-adjusted reductions in FPG in the 3 liraglutide groups were -49 mg/dL, -61 mg/dL, and -61 mg/dL, respectively (all P<.0001 vs placebo). Nearly half of the subjects in the liraglutide 1.9 mg group achieved the ADA goal for postprandial glucose of 180 mg/dL. The fasting glucagon concentration was significantly reduced in the liraglutide 1.9 mg group compared with placebo (-3.26 pM; P=.0497). Among subjects in the liraglutide groups, 7% to 15% withdrew, compared with 28% of the placebo subjects. Nausea occurred in 10% of the subjects in the liraglutide 0.65 and 1.9 mg groups compared with 2% to 3% in the liraglutide 1.25 mg and placebo groups, respectively. There was no treatment-related induction of anti-liraglutide antibodies and no minor or major hypoglycemic episodes occurred. Weight loss of 3 kg occurred with liraglutide 1.9 mg.

Five placebo-controlled trials were part of a comprehensive phase 3 (LEAD, Liraglutide Effect and Action in Diabetes) program. The LEAD program randomized nearly 4000 subjects with T2DM who previously had been managed with treatments ranging from diet and exercise alone to one or more OADs. Doubleblind treatment ranged from 26 to 52 weeks with liraglutide in doses of 0.6, 1.2, or 1.8 mg administered once daily. Subjects randomized to either 1.2 or 1.8 mg were started on 0.6 mg with uptitration in 0.6 mg increments at the end of each week until the allocated dose was reached. Furthermore, 2 of these trials have ongoing open-label extensions.

A 52-week monotherapy phase 3 trial demonstrated a durable glycemic response to liraglutide alone compared with glimepiride 8 mg in 746 subjects previously treated with diet and exercise or OAD monotherapy.¹⁷ Liraglutide 1.2 and 1.8 mg once daily reduced A1C levels by 0.8% and 1.1%, respectively, compared with an 0.5% reduction with glimepiride 8 mg once daily (both liraglutide doses P<.05 vs glimepiride). In addition, subjects who were previously on a diet and exercise treatment regimen (drug-naïve) experienced a reduction in A1C levels of 1.2% and 1.6% with liraglutide 1.2 mg and 1.8 mg, respectively (both liraglutide doses P<.05 vs glimepiride). Among subjects treated with either liraglutide 1.2 and 1.8 mg, respectively, 43% and 51% achieved an A1C level <7.0%, compared with 28% of patients treated with glimepiride (both P<.05 vs glimepiride). FPG levels declined by 15, 26, and 5 mg/dL in patients treated with liraglutide 1.2 and 1.8 mg and glimepiride, respectively (both liraglutide doses P<.05 vs glimepiride). PPG levels declined 31, 37, and 25 mg/dL, respectively (P<.05 for liraglutide 1.8 mg vs glimepiride). Body weight decreased by 2.1 and 2.5 kg in subjects treated with liraglutide 1.2 and 1.8 mg patients, respectively, compared with an increase of 1.1 kg in subjects treated with glimepiride (both liraglutide doses P<.05 vs glimepiride). Nausea was reported by 28% and 29% of subjects treated with either liraglutide 1.2 or 1.8 mg, respectively, and 9% of subjects treated with glimepiride. Minor hypoglycemia (plasma glucose <56 mg/dL) was reported by 12% and 8% of subjects treated with either liraglutide 1.2 or 1.8 mg vs 24% of subjects treated with glimepiride. No episodes of major hypoglycemia were reported.

A 26-week trial of once-daily treatment with liraglutide in combination with metformin produced significant improvements in glycemic control beyond previous OAD monotherapy (35%) or combination therapy (65%). This placebo-controlled trial randomized 1091 subjects with T2DM previously treated with one or more OADs to either liraglutide 0.6, 1.2, or 1.8 mg once daily plus metformin 1 g twice daily; placebo plus metformin; or glimepiride 4 mg once daily plus metformin.¹⁸ All doses of liraglutide had significantly greater efficacy than placebo (TABLE 2). Liraglutide 1.2 and 1.8 mg doses plus metformin significantly reduced A1C by 1.0% compared with an increase of 0.1% with metformin (P<.05) and a comparable decrease with metformin plus glimepiride (1%).¹⁸ (See TABLE 2 for complete efficacy and safety results for all treatments except liraglutide 0.6 mg.) Weight loss of 2.6 to 2.8 kg occurred in the 2 liraglutide plus metformin groups, compared with a 1.5 kg decrease in the metformin group (P<.05 for both liraglutide doses vs metformin). The weight loss with liraglutide contrasted with a weight gain of 0.9 kg in the metformin plus glimepiride group (P<0.05).¹⁸ Nausea was initially reported in 6% to 12% of subjects in the liraglutide plus metformin groups but declined to 2% (same as the metformin group) after 8 to16 weeks of treatment. The incidence of minor hypoglycemia was relatively low (0.8%-3.7%) with liraglutide plus meformin, or placebo plus metformin, whereas a higher incidence (17%) was observed with metformin plus glimepiride.¹⁸ No major hypoglycemic episodes occurred with any treatment.

A comparison of liraglutide 0.6, 1.2, or 1.8 mg once daily combined with glimepiride 2 to 4 mg once daily, placebo plus glimepiride, or rosiglitazone plus glimepiride was also studied over 26 weeks.¹⁹ Significantly greater reductions in A1C (-0.6 to 1.1) levels were observed with all liraglutide doses plus glimepiride (P<.0001) compared with placebo plus glimepiride (0.2%) at the end of 26 weeks. The reductions in A1C were greater with liraglutide 1.2 or 1.8 mg plus glimepiride (1.1%) compared with rosiglitazone plus glimepiride (0.4%; P<.0001). Similarly, greater reductions in FPG were observed with liraglutide 1.2 mg and 1.8 mg plus glimepiride (-28 and -29 mg/dL) compared with placebo plus glimepiride (+18 mg/dL; P<.0001) or rosiglitazone plus glimepiride (-16 mg/dL; P<.0001). Once-daily treatment with liraglutide in doses of 0.6 to 1.8 mg plus glimepiride once daily led to weight stabilization or a slight weight gain, which may have resulted from the weight-inducing effects of glimepride.¹⁹ Nausea occurred in 5% to11% of subjects treated with liraglutide plus glimepiride compared with 2% to 3% of subjects treated with either glimepiride, or rosiglitazone plus glimepiride. Minor hypoglycemia was observed in fewer than 10% of subjects with all treatments. Antibodies to liraglutide were detected in 9 to13% of subjects treated with liraglutide.

The LEAD program also investigated the efficacy and safety of once-daily liraglutide in combination with 2 OADs. A 26-week placebo-controlled trial of liraglutide 1.8 mg once daily added to metformin plus glimepiride led to a significantly greater reduction in A1C levels than did insulin glargine added to metformin and glimepiride (1.3% vs 1.1%, respectively; P<.05), or placebo added to metformin and glimepiride (0.2%). The reduction in FPG levels was similar (28 vs 32 mg/dL, respectively) between the liraglutide and glargine groups.²⁰ The change in body weight was significantly more favorable with liraglutide compared with glargine (-1.8 vs +1.6 kg, respectively; P<.05). Nausea occurred in 15% of subjects in the liraglutide plus metformin and glimepiride group compared with 3.5% in the metformin and glimepiride group, and 1.3% in the glargine plus metformin and glimepiride group. The incidence of minor hypoglycemia was similar between the liraglutide (27%) and glargine (28%) groups but 5 subjects treated with liraglutide in combination with metformin and glimepiride reported a major hypoglycemic episode; only one required medical assistance and none resulted in coma or seizures. Anti-liraglutide antibodies were detected in 10% of subjects treated with liraglutide.

Another placebo-controlled trial investigated the addition of liraglutide 1.2 or 1.8 mg once daily to metformin 1 g and rosiglitazone 4 mg, both OADs twice daily.²¹ A1C levels decreased by 1.5% in both groups where liraglutide was added, compared with 0.5% for the metformin plus rosiglitazone group (P<.05 for both liraglutide groups vs metformin plus rosiglitazone). FPG levels decreased 40 and 43 mg/dL in the liraglutide groups, respectively, compared with 7 mg/dL in the metformin plus rosiglitazone group (P<.05 for both liraglutide groups vs metformin plus rosiglitazone). Reductions in PPG levels similar in magnitude to those seen with FPG were observed. Nausea was the most common adverse event. Minor hypoglycemia occurred in 8% to 9% of patients treated with liraglutide plus metformin and rosiglitazone and 5% of subjects treated with metformin and rosiglitazone. No major hypoglycemic episodes occurred.

The glucose-lowering effect produced by liraglutide is associated with improvements in several of the pathophysiologic mechanisms contributing to T2DM. Improvement in measures such as the proinsulin:insulin ratio is indicative of an increase in pancreatic β-cell function.^14,22 Vilsboll et al observed significant improvement in the median change from baseline in the insulin:proinsulin ratio with several doses of liraglutide compared with placebo (1.90 mg: -0.19, P=.0111; 1.25 mg: -0.28, P=.0062; 0.65 mg: -0.15, P=.0218). In a 9-day, placebo-controlled study, glucose sensitivity and insulin secretion were both increased compared to baseline (42%, P<.01 and 70%, P<.0005, respectively) following administration of liraglutide 6 mcg/kg once daily.¹⁶

FPG and nocturnal glucose levels were reduced by 11% (P=NS) and 18% (P<.01), respectively.

Three LEAD trials also demonstrated that liraglutide treatment for 26 weeks improves various markers of β-cell function. The addition of liraglutide 1.8 mg once daily to either metformin 1 g twice daily, glimepiride 4 mg once daily, or the combination of metformin and glimepiride, led to a 28% to 34% improvement (P<.03 vs comparators for each of the 3 liraglutide 1.8 mg groups) in pancreatic β-cell function (as measured by the homeostasis model assessment of β-cell function).²³ Liraglutide has also been shown to improve the first- and second-phase insulin responses.²⁴ Subjects with T2DM treated with liraglutide 1.25 mg or 1.9 mg once daily for 14 weeks exhibited a 118% and 103% increase, respectively, in the first-phase insulin response compared with placebo (P=.02 and P=.05 vs placebo, respectively). Second-phase insulin response increased by 79% in the liraglutide 1.25 mg group compared with placebo (P=.005).

Body weight is reduced with liraglutide, with a loss of up to 2.5 kg after 52 weeks of monotherapy.¹⁷ Body composition analysis indicates that the loss in weight is due to a reduction in visceral and subcutaneous fat mass, whereas lean mass has been noted to increase slightly.¹⁵ The decrease in fat mass included central body visceral and subcutaneous adipose tissue.²⁵

Reductions in triglyceride levels (15% to 22%, P=NS to P=.011 vs placebo) have been observed with liraglutide monotherapy in daily doses ranging from 0.65 to 1.9 mg.¹⁴ The same study showed a reduction of 5 to 8 mm Hg in systolic blood pressure (P=.042 vs placebo).¹⁴

The LEAD studies also showed beneficial effects on blood pressure with liraglutide compared with other glucose-lowering agents in three 26-week trials. Compared with a combination of metformin 2 g per day and glimepiride 4 mg per day, liraglutide 1.8 mg once daily plus metformin 2 g per day reduced systolic blood pressure by 2.7 mm Hg (P<.05).²⁶ Compared with insulin glargine in combination with metformin and glimepiride, a reduction in the systolic blood pressure of 4.5 mm Hg was observed with liraglutide 1.8 mg in combination with metformin and glimepiride (P<.05). These reductions occurred after 2 weeks of treatment and were not due to weight loss. When compared with the combination of rosiglitazone plus glimepiride, or placebo plus glimepiride, the reduction in systolic blood pressure with liraglutide in combination with glimepiride was not significantly different. Changes in diastolic blood pressure were not significantly different among the various treatment groups in the 3 trials.

Efficacy and safety of liraglutide compared with glimepiride when added to metformin

  The DPP-4 inhibitors

Sitagliptin

Various trials have compared the DPP-4 inhibitor sitagliptin (in doses ranging from 5 mg twice daily to 200 mg once daily) with placebo and glipizide in trials ranging from 12 to 24 weeks in duration.^27-31 Sitagliptin has been studied as monotherapy or in combination with one or more OADs. Treatment with sitagliptin was shown to reduce A1C levels by 0.2% to 0.9% and FPG levels by 11 to 18 mg/dL. FIGURE 2 illustrates the efficacy of sitagliptin 100 mg once daily versus placebo, when added to metformin therapy, in reducing A1C and FPG levels over a period of 24 weeks.²⁹ Reductions in A1C and FPG are similar with sitagliptin 100 mg once daily alone or in combination with other agents. For example, at 24 weeks, monotherapy with sitagliptin 100 mg once daily reduced A1C levels from 8.0% to 7.4% compared to an increase from 8.0% to 8.2% for placebo (P≤.001).²⁸ When added to metformin 1500 mg or more per day, sitagliptin 100 mg once daily reduced the A1C from 8.0% to 7.3%, whereas the A1C remained at 8.0% with placebo (P<.001), whereas the addition of sitagliptin 100 mg once daily to pioglitazone 30 mg to 45 mg per day reduced the A1C from 8.1% to 7.2% compared with 8.0% to 7.8% for pioglitazone plus placebo (P<.001).^29-30 Similarly, FPG levels were reduced from 171 to 159 mg/dL (P≤.001 vs placebo), 169 to 151 mg/dL (P<.001 vs metformin plus placebo, and 168 to 150 mg/dL (P<.001 vs pioglitazone plus placebo).^28-30 Monotherapy with sitagliptin 100 mg once daily significantly reduced PPG levels by 41 mg/dL (P≤.01 vs placebo).²⁷

The improvement in glycemic control seen with sitagliptin may result in part from increased insulin secretion, as well as an improvement in the proinsulin: insulin ratio.^27-30 An increase in insulin levels of 7.8 pM has been observed with sitagliptin 100 mg once daily compared with a decrease of 1.2 pM with placebo.²⁹ A reduction of 0.02 to 0.11 in the proinsulin:insulin ratio also has been seen, suggesting an improvement in β-cell function.^27-30

Sitagliptin 50 mg twice daily has also been shown to reduce triglycerides (10% [P<.05 vs placebo] and free fatty acids (18% [P< .05 vs placebo]) compared with placebo.³¹ At the same time, high-density lipoprotein cholesterol increased 4% (P< .05 vs placebo). Sitagliptin was shown to cause little, if any, increase in body weight.

The incidence of hypoglycemia has been shown to range from 0% to 4.1% with sitagliptin versus 0% to 2.4% with placebo, whereas the incidence of overall gastrointestinal disturbances observed is 9.2% to 16.4% with sitagliptin versus 6.2% to 14.5% with placebo.^27-31 Serious hypersensitivity reactions (anaphylaxis, angioedema, and exfoliative skin conditions) have been reported within the first 3 months of sitagliptin therapy, sometimes after the first dose. Treatment should be discontinued if such an event is suspected.³

A cost-effectiveness analysis compared the addition of sitagliptin, rosiglitazone, or a sulfonylurea to metformin therapy in patients with T2DM who were not at glycemic goal (A1C >6.5%).³² The study demonstrated that sitagliptin plus metformin was cost-effective compared with a sulfonylurea plus metformin, and that sitagliptin plus metformin was cost-saving with improved health outcomes versus rosiglitazone plus metformin.

Vildagliptin, alogliptin, and saxagliptin

Three DPP-4 inhibitors may be available in the near future. Alogliptin is currently under FDA review, and saxagliptin is in phase 3 clinical trials. The FDA review of vildagliptin has focused on concerns regarding adverse skin events and elevated liver enzymes.

Two double-blind, 24-week studies have investigated monotherapy with vildagliptin in drug-naïve patients with T2DM. One study randomized patients to vildagliptin 50 mg once daily, 50 mg twice daily, 100 mg once daily, or placebo.³³ The respective changes in the A1C level were 8.3% to 7.9% (P=.011 vs placebo), 8.4% to 7.7% (P<.001 vs placebo), 8.3% to 7.5% (P<.001 vs placebo) compared with 8.5% to 8.4% with placebo. Reductions from baseline to 24 weeks in the FPG were 9 mg/dL (P=NS vs placebo), 22 mg/dL (P=.001 vs placebo), and 20 mg/dL (P=.001 vs placebo) compared with 2 mg/dL with placebo. Similar reductions in A1C were observed when vildagliptin 50 mg twice daily was compared with rosiglitazone 8 mg once daily (1.1% vs 1.3%; P=NS).³⁴ The reduction in A1C was greater in both groups of patients with a baseline A1C >9.0%. The reduction in FPG was greater with rosiglitazone compared with vildagliptin (41 vs 23 mg/dL; P<.001).

The addition of metformin in daily doses of ≥1500 mg/day further improved glycemic control over vildagliptin monotherapy, with FPG reductions ranging from 14 to 38 mg/dL.^35-37 The corresponding decrease in A1C ranged from 0.5% to 1.2%. The combination of vildagliptin with pioglitazone in low (50 mg/15 mg) and high (100 mg/30 mg) doses reduced FPG levels to a greater extent (43 mg/dL and 50 mg/dL, P=.022 and P<.001, respectively, vs pioglitazone monotherapy) than did vildagliptin or pioglitazone alone (23 mg/dL, 34 mg/dL, respectively).³⁸

The combination of vildagliptin plus metformin has been shown to increase insulin levels by 40 pM (adjusted for placebo; P=.015), suggesting that this combination improves β-cell function.³⁷

The most common AEs associated with vildagliptin appear to be headache, dizziness, and nasopharyngitis, with an incidence similar to placebo (TABLE 1).^33,39,40 Hypoglycemia occurred in <1% of patients with 1.95 events/patient-year compared with 2.96 events/patient-year for placebo.⁴⁰ However, because of adverse skin events and elevated liver enzymes, the future commercial availability of vildagliptin in the United States remains unclear.⁴¹

Clinical data in patients with T2DM indicate that alogliptin and saxogliptin share many of the same attributes as the other DPP-4 inhibitors (TABLE 1). In a randomized, double-blind, placebo-controlled study, 14 days of once-daily treatment with alogliptin in doses ranging from 25 to 400 mg lowered A1C and PPG levels.⁴²

A1C levels were reduced from baseline with alogliptin 25 mg (7.9% to 7.7%, P=.04 vs placebo), 100 mg (7.7% to 7.3%, P<.001 vs placebo), and 400 mg (8.0% to 7.7%, P=.02 vs placebo) compared with no change for placebo. PPG levels after dinner were reduced by 22 mg/dL (P=.017 vs placebo), 40 mg/dL (P<.001 vs placebo), and 35 mg/dL (P=.003 vs placebo), respectively, compared with an increase of 13 mg/dL for placebo. Alogliptin was well-tolerated. Headache, dizziness, and constipation were the most frequently observed but did not cause discontinuation. Two cases of symptomatic hypoglycemia occurred in alogliptin-treated patients, with one case being treatment-emergent. Slightly greater reductions in A1C were observed with alogliptin 12.5 or 25 mg once daily (both 0.6%; P<.001 vs placebo) compared with placebo for 26 weeks in patients inadequately controlled with diet and exercise alone.⁴³

Saxagliptin has been investigated in 2 randomized, double-blind, placebo-controlled studies involving drug-naïve patients with T2DM.^44,45 In one study, patients received saxagliptin 2.5, 5, 10, 20, or 40 mg once daily (low-dose cohort) or placebo for 12 weeks. A high-dose cohort received saxagliptin 100 mg once daily or placebo for 6 weeks. In the low-dose cohort, A1C was reduced by 0.7% to 0.9% compared with a reduction of 0.3% with placebo (P<.007 vs placebo). Similarly, FPG and PPG were reduced 11 mg/dL to 22 mg/dL and 24 mg/dL to 41 mg/dL, respectively, in the low-dose cohort compared with an increase of 3 mg/dL and a decrease of 1 mg/dL, respectively, with placebo. In the high-dose cohort, the A1C, FPG, and PPG levels were reduced by 1.1%, 26 mg/dL, and 45 mg/dL at the end of 6 weeks.

  summary

Acting on several of the mechanisms that contribute to T2DM, GLP-1 receptor agonists and DPP-4 inhibitors increase insulin secretion, decrease glucagon secretion, and enhance β-cell function. Consequently, they are variably effective in improving all measures of glycemic control—A1C, FPG, and PPG levels—in patients with T2DM, including those previously managed only with diet and exercise. As monotherapy, the GLP-1 receptor agonists improve both fasting and postprandial glucose, with an average A1C reduction of 0.5% to 1.0% for exenatide and 0.5% to 1.6% for liraglutide. Average reductions of the A1C with the DPP-4 inhibitors range from 0.5% to 0.8%. When a GLP-1 receptor agonist or DPP-4 inhibitor is added to existing glucose-lowering treatment with one or more oral agents or insulin, further improvement in glycemic control is observed.

These data demonstrate that the GLP-1 receptor agonists and the DPP-4 inhibitors can be used at any stage of T2DM, including drug-naïve patients. Because incretins improve markers of β-cell function, they may have the potential to limit disease progression. Long-term studies are required to verify this.

The GLP-1 receptor agonists promote weight loss of up to 3 to 4 kg, whereas the DPP-4 inhibitors are weight neutral or cause slight weight gain. At the same time, all these agents generally exhibit a good safety profile with a low incidence of mostly mild to moderate adverse events. The occurrence of hypoglycemia is low and severe hypoglycemia is infrequent, although the risk increases when a sulfonylurea is included in the regimen.

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The Journal of Family Practice ©2008 Quadrant HealthCom Inc. and Primary Care Education Consortium